Designed Molecules Trap Cancer Cells in Deadly Cages

Chemists have designed a carbohydrate-based molecule that can surround and strangle bone cancer cells by self-assembling into a tangled web of nanofibers (J. Am. Chem. Soc. 2014, DOI: 10.1021/ ja5111893). The molecule spares healthy cells because its assembly is triggered by an enzyme that’s overexpressed on cancer cells.

The inspiration for spinning a molecular cage around cells came from nature, says Rein V. Ulijn of the City University of New York’s Hunter College. Many of the body’s cells are enmeshed in an extracellular matrix—a complex web of biomolecules that provides structure for tissues, facilitates intercellular communication, and traps nutrients. Scientists are developing molecules that spontaneously assemble into simpler versions of this matrix to provide a growth medium for cells, in particular for tissue engineering.

The field has focused mainly on self-assembling peptides. In a recent study, Bing Xu of Brandeis University and colleagues designed a nonnurturing peptide that aggregates and engulfs cancer cells only when its phosphate group is removed (Angew. Chem. Int. Ed. 2014, DOI: 10.1002/anie.201402216). The phosphate-free peptides have a hydrophilic end and a hydrophobic one, which allow them to assemble like lipids in a cell membrane. The negative charge on the phosphate groups creates electrostatic repulsion between the molecules and prevents this. This phosphate on-off switch is great for targeting cancer because some types of cancer cells overexpress alkaline phosphatase, an enzyme that cleaves phosphates.

Ref : http://onlinelibrary.wiley.com/doi/10.1002/anie.201402216/abstract

Designed Molecules Trap Cancer Cells in Deadly Cages 

Neuroptis reports positive results from ML7 pre-clinical trial for treatment of dry eye syndrome

Neuroptis, a company specialized in the development of drugs to treat eye disorders, today announces positive results from a second animal trial of its preservative-free ML7 eye drops. ML7 is intended for use in the treatment of eye surface diseases, particularly dry eye syndrome.

Both animal trials demonstrated excellent local tolerance and very low systemic absorption. In the first trial conducted in rats by Iris Pharma, following seven days of treatment the ML7 (see structure) eye drops were statistically more effective than the placebo.

The second trial, conducted with the Charles River CRO in Boston, MA, involved rabbits showing significant inflammation of the cornea. In the group treated with ML7 eye drops, the tarsal (or meibomian) glands were seen to return to normal, with no further inflammation or dilation and a protective effect was observed. This is the first time that such results have been seen.

To launch the clinical trials the company will begin production of clinical batches through a subcontractor and will submit applications for approval by the European Medicines Agency (EMA) and local patient protection committees.

Neuroptis reports positive results from ML7 pre-clinical trial for treatment of dry eye syndrome

Study: Prostate cancer drug stabilizes memory loss for a year in women with Alzheimer's disease

Women with Alzheimer's disease showed stable cognition for a year when a drug that is more commonly used to treat advanced prostate cancer was added to their drug regimen, according to a new study from researchers at the University of Wisconsin-Madison.

"This is the first time any therapy has been shown to stabilize memory loss over a year," says Dr. Craig Atwood, co-lead author of the study and associate professor of medicine at the UW School of Medicine and Public Health.

 

The study was published today in the Journal of Alzheimer's Disease and is available here: http://iospress.metapress.com/content/n207096671247200.

The clinical trial, initiated by Dr. Richard Bowen at the former Voyager Pharmaceutical Corporation, followed 109 women with mild to moderate Alzheimer's disease. Some were treated with the drug leuprolide acetate (Lupron Depot first above structure), used to treat cancer in men and severe endometriosis in women, and with an acetylcholineesterase inhibitor such as Aricept (second below structure), which improves mood in people with the condition but does little to slow memory loss. Others taking an acetylcholineesterase inhibitor received low-dose Lupron alone or a placebo.

Study: Prostate cancer drug stabilizes memory loss for a year in women with Alzheimer's disease

Researchers uncover mechanism by which anti-inflammatory processes may cause Alzheimer's

Inflammation has long been studied in Alzheimer's, but in a counterintuitive finding reported in a new paper, University of Florida researchers have uncovered the mechanism by which anti-inflammatory processes may trigger the disease.

This anti-inflammatory process might actually trigger the build-up of sticky clumps of protein that form plaques in the brain. These plaques block brain cells' ability to communicate and are a well-known characteristic of the illness.

The finding suggests that Alzheimer's treatments might need to be tailored to patients depending on which forms of Apolipoprotein E, a major risk factor for Alzheimer's disease, these patients carry in their genes.

The researchers have shown that the anti-inflammatory protein interleukin 10, or IL-10, can actually increase the amount of apolipoprotein E, or APOE, protein -- and thereby plaque -- that accumulates in the brain of a mouse model of Alzheimer's, according to the study, published online today (Jan. 22) in the journal Neuron.

Researchers uncover mechanism by which anti-inflammatory processes may cause Alzheimer's

Eribulin effective in metastatic breast cancer, researchers find

An  international research team, led by Dartmouth's Peter A. Kaufman, MD, published findings in the Journal of Clinical Oncologydemonstrating that, while not superior to capecitabine, eribulin is an active and well-tolerated therapy in women with metastatic breast cancer (MBC) receiving this therapy as a first, second, or third line chemotherapy regimen. Additionally, these patients had all been previously treated with both an anthracycline and a taxane in either the adjuvant or metastatic setting. This study is the first to address the use of eribulin early in the course of metastatic breast cancer, specifically either the first or second line setting

 

"Additionally, it is of great interest that subset analysis suggests that eribulin may be particularly active and effective in triple negative MBC, which is known to be an aggressive subset of breast cancer, and one associated unfortunately with a particularly poor prognosis overall," said Kaufman.

Eribulin has been approved in numerous countries in the third line or latter setting for the treatment of MBC, and is increasingly widely used. It is the only chemotherapeutic agent shown to have a survival benefit for patients with MBC in the third line or latter chemotherapeutic setting. Given previous research findings, and now findings from this large international trial, there has been great interest from oncologists and other clinicians in the potential impact that eribulin might have earlier in the course of MBC.

This phase III randomized trial assigned 1,099 women who had previously been treated with an anthracycline or a taxane to either eribulin or capecitabine as their first, second, or third line chemotherapy for advanced MBC. Stratification factors were human epidermal growth factor receptor-2 (HER2) status and geographic region. Coprimary endpoints were overall survival and progression-free survival.

"While there is not a statistically significant difference in overall survival with eribulin in comparison to capecitabine, the median overall survival seen with eribulin is in fact numerically slightly superior to that of capecitabine," explained Kaufman.

Ref : http://jco.ascopubs.org/content/early/2015/01/20/JCO.2013.52.4892

Eribulin effective in metastatic breast cancer, researchers find  

Can coffee protect against malignant melanoma? Study looks at trends .............

Both epidemiological and pre-clinical studies have suggested that coffee consumption has a protective effect against non-melanoma skin cancers. However the protective effect for cutaneous melanoma (malignant and in situ) is less clear, according to a study published January 20 in the JNCI: Journal of the National Cancer Institute.

To determine if there is an association between coffee consumption and risk of cutaneous melanoma, Erikka Loftfield, M.P.H., of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, and colleagues used data from the NIH-AARP Diet and Health Study. Information on coffee consumption was obtained from 447,357 non-Hispanic white subjects with a self-administered food-frequency questionnaire in 1995/1996, with a median follow-up of 10 years. All subjects included in the analysis were cancer-free at baseline, and the authors adjusted for ambient residential ultraviolet radiation exposure, body mass index, age, sex, physical activity, alcohol intake, and smoking history.

Overall, the highest coffee intake was inversely associated with a risk of malignant melanoma, with a 20% lower risk for those who consumed 4 cups per day or more. There was also a trend toward more protection with higher intake, with the protective effect increasing from 1 or fewer cups to 4 or more. However, the effect was statistically significant for caffeinated but not decaffeinated coffee and only for protection against malignant melanoma but not melanoma in-situ, which may have a different etiology.

The researchers point out that the results are preliminary and may not be applicable to other populations, and therefore additional investigations of coffee intake are needed. However, they conclude that "Because of its high disease burden, lifestyle modifications with even modest protective effects may have a meaningful impact on melanoma morbidity.

Ref : http://jnci.oxfordjournals.org/content/107/2/dju421

Can coffee protect against malignant melanoma? Study looks at trends   

Kinex Pharmaceuticals doses first actinic keratosis patient with KX2-391 ointment

Kinex Pharmaceuticals announced today that the first actinic keratosis patient has been dosed with KX2-391 ointment in Austin, Texas.

KX2-391 (KX01), a dual Src/pre-tubulin inhibitor, is a small molecule drug that has excellent skin penetration when formulated as a topical ointment. The pre-tubulin activity causes hyperproliferating cells to undergo apoptosis due to a disruption of the tubulin dynamics needed for these cells to pass through mitosis. Actinic Keratosis (AK) is a very common skin disease that appears as rough, dry, scaly patches or growths that form on the skin when the skin is badly damaged by ultraviolet rays from the sun or through indoor tanning. Ultraviolet rays can cause damage to DNA and RNA leading to keratinocyte mutations and uncontrolled growth. Reduction of the tumor suppressor p53 level has also been implicated in the unchecked proliferation of dysplastic keratinocytes. KX2-391 also potently increases p53 levels during unchecked proliferation thereby potentially addressing the dysregulation of p53 in AK.

Dr. Rudolf Kwan, Chief Medical Officer of Kinex Pharmaceuticals commented "Actinic Keratosis is a common dermatological problem with long term overexposure to the sun's ultraviolet light. If left untreated, AK can progress to squamous cell carcinoma, a type of skin cancer. Once a patient is afflicted with AK lesions, they tend to continue getting new AK lesions for life. We are hopeful to offer a new treatment option for these patients."

Kinex Pharmaceuticals doses first actinic keratosis patient with KX2-391 ointment

LUME-Lung 1 shows QoL, symptoms benefits

LUME-Lung 1 (Nintedanib + docetaxel) trial patients’ reports of symptoms and health-related quality of life (HRQoL) support the use of second-line nintedanib for the treatment of advanced non-small-cell lung cancer (NSCLC).

Initial findings from the phase III trial demonstrated that the angiokinase inhibitor plus docetaxel offered significantly better progression-free survival for patients with advanced NSCLC, including subpopulations with adenocarcinoma, than placebo plus docetaxel, explain Silvia Novello (University of Turin, Italy) and co-authors in theEuropean Journal of Cancer.

For the current study, the team used a battery of tests to compare patient-reported outcomes on day 1 of each 21-day treatment cycle, at the end of treatment and at the first follow-up visit for the two treatment groups.

Over 80% of the 655 nintedanib-treated patients and 659 of controls completed the European Organisation for Research and Treatment of Cancer Core QoL Questionnaire and its lung cancer supplement, with 70% doing so at the end of treatment.

Baseline health and QoL were comparable for the nintedanib and placebo groups with relatively good scores and a low burden of lung cancer-specific symptoms, such as cough and pain.

The patient groups also had comparable time to deterioration for cough, pain and dyspnoea, although patients given nintedanib had a significantly shorter time to development of the gastrointestinal symptoms of nausea, vomiting, diarrhoea and decreased appetite.

Similarly, the 322 patients with adenocarcinoma histology given nintedanib alongside docetaxel had a similar time to deterioration of lung cancer symptoms as the 336 given placebo, with a small benefit in global health and QoL with nintedanib detected but this did not reach significance.

Ref : http://www.ejcancer.com/article/S0959-8049(14)01139-3/fulltext

LUME-Lung 1 shows QoL, symptoms benefits

PharmaMar to begin PM1183 Phase III trial in combination with doxorubicin in SCLC

In continuation of my update on PM 1183 and doxorubicin

Zeltia announces today that its pharmaceutical division PharmaMar will start a Phase III trial with PM1183 in combination with doxorubicin against topotecan in SCLC, given the activity observed in an interim analysis of an ongoing Phase Ib trial. The results of this study will be presented at a prominent international cancer meeting this year, which will be soon announced.

Patients with small cell lung cancer (SCLC) after failure of standard chemotherapy, as well as bladder, gastric, breast, endometrial or ovarian cancer, neuroendocrine tumors and soft-tissue sarcomas were treated with the combination in a Phase I. The treatment showed efficacy across all cancer types, including several complete responses. This clinical response was remarkable in certain tumor types, particularly in SCLC, and consequently more patients with this type of tumor were enrolled. The treatment was generally well-tolerated, and these patients had marked objective tumor responses and were able to receive several cycles of treatment.

"The data we have are very exciting as patients with SCLC have the worst prognosis among lung cancer patient. There have been no significant advances in 25 years in this type of lung cancer." says Luis Mora, Managing Director, PharmaMar.

Topotecan, which is the only drug approved in the EU and the US for the treatment of SCLC in second line, achieved objective responses in only 20-25% of the patients (depending on the response to initial treatment)1. Preliminary results presented last year at the 15th World Conference on Lung Cancer showed that 71% of SCLC patients responded to PM1183 plus doxorubicin as second-line therapy. PharmaMar will start a head-to-head study to compare the combination against topotecan for this indication.

PharmaMar to begin PM1183 Phase III trial in combination with doxorubicin in SCLC

Researchers reveal how melanoma becomes resistant to promising new drug combo therapy

In a new study led by UCLA Jonsson Comprehensive Cancer Center member Dr. Roger Lo, researchers have uncovered how melanoma becomes resistant to a promising new drug combo therapy utilizing BRAF+MEK inhibitors in patients after an initial period of tumor shrinkage.

During the new two-year study, Lo and his team took 43 tumor samples from 15 patients before they were prescribed the new BRAF+MEK inhibitor combo drugs and then after they relapsed due to the melanoma developing drug resistance. The participants had all benefited from the combo therapy initially, but after periods of time the tumors regressed.

All the tumors biopsied from the patients were subjected to in-depth analysis of the genetic material extracted from the tumors. This analysis of patient-derived tumors then provided leads for the investigators to study how melanoma cells grown in Lo's laboratory rewired their growth circuitry to get around the combo inhibitors.

Researchers reveal how melanoma becomes resistant to promising new drug combo therapy

Study suggests that antibiotics may help fight norovirus

Antibiotics aren't supposed to be effective against viruses. But new evidence in mice suggests antibiotics may help fight norovirus, a highly contagious gastrointestinal virus, report scientists at Washington University School of Medicine in St. Louis.

The researchers found antibiotics could help prevent norovirus infections. The same team also showed that a recently identified immune system molecule can cure persistent norovirus infections even in mice with partially disabled immune systems. The surprising findings, available online in Science, will appear Jan. 16 in the journal's print edition.

Outbreaks of norovirus are notoriously difficult to contain and can spread quickly on cruise ships and in schools, nursing homes and other closed spaces.

The researchers found that norovirus works its way into gut tissue in mice that have been pretreated with antibiotics but that the virus cannot establish a persistent infection. Follow-up studies showed that norovirus needs a bacterial collaborator to establish a persistent infection in the gut. Eradicating the bacterial partner with an antibiotic can prevent persistent norovirus infection in mice.

"The virus actually requires the bacteria to create a persistent infection," said senior author Herbert W. Virgin IV, MD, PhD, the Edward Mallinckrodt Professor of Pathology and head of the Department of Pathology and Immunology. "The virus appears to have a symbiotic relationship with the bacteria they share the job of establishing persistence."

Study suggests that antibiotics may help fight norovirus

TSRI scientists identify novel synthetic compound that reduces activity of a cancer-related protein

Scientists from the Florida campus of The Scripps Research Institute (TSRI) have identified a novel synthetic compound that sharply inhibits the activity of a protein that plays an important role in in the progression of breast and pancreatic cancers.

In the new study, to be published in the February 2015 print edition of the journal Molecular Pharmacology, the scientists showed that the compound, known as SR1848, reduces the activity and expression of the cancer-related protein called "liver receptor homolog-1" or LRH-1.

"Our study shows that SR1848 removes LRH1 from DNA, shutting down expression of LRH-1 target genes, and halts cell proliferation," said Patrick Griffin, chair of the TSRI Department of Molecular Therapeutics and director of the Translational Research Institute at Scripps Florida. "It's a compound that appears to be a promising chemical scaffold for fighting tumors that are non-responsive to standard therapies."

TSRI scientists identify novel synthetic compound that reduces activity of a cancer-related protein

FDA grants orphan drug status to NBI-77860 for treatment of congenital adrenal hyperplasia

Neurocrine Biosciences, Inc. (NASDAQ: NBIX) announced that NBI-77860, a proprietary corticotropin releasing factor 1 (CRF) receptor antagonist, has been granted orphan drug status by the United States Food and Drug Administration (FDA) for the treatment of congenital adrenal hyperplasia (CAH) a disease that affects approximately 20,000-30,000 people in the United States.

"We are very pleased that the FDA has granted NBI-77860 orphan status to treat congenital adrenal hyperplasia, a devastating disease that is a significant challenge for both clinicians and patients," said Malcolm Lloyd-Smith, Chief Regulatory Officer of Neurocrine Biosciences. "This status represents a significant regulatory milestone for the CAH program and underscores the importance of bringing a safe and effective CAH therapy to market. We look forward to the results from our recently initiated 1401 Study of adolescents with classic CAH, in 2015."

FDA grants orphan drug status to NBI-77860 for treatment of congenital adrenal hyperplasia

Long-acting drug effectively prevents HIV-like infection in monkeys

Cabotegravir (USAN  and INN ) (also known as S/GSK1265744 or previously referred to by the research code GSK744) is an investigational new drug under development for the treatment of HIV infection. It is an integrase inhibitor, with a carbamoyl pyridone structure similar to dolutegravir. In investigational studies, the agent has been packaged intonanoparticles (GSK744LAP) conferring an exceptionally long half-life of 21–50 days following a single dose. In theory, this would make possible suppression of HIV with dosing as infrequently as once every three months.

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HIV researchers hope a new compound, known as cabotegravir, could make dosing easier for some because the drug would be administered by injection once every three months. A clinical trial testing long-acting cabotegravir's safety and acceptability has already begun at multiple U.S. sites including The Rockefeller University Hospital. Meanwhile two new studies, including one conducted by researchers at the Aaron Diamond AIDS Research Center (ADARC) and Rockefeller University, published today (January 15) inScience Translational Medicine, show that long-acting cabotegravir injections are highly protective in a monkey model of vaginal transmission of a virus similar to HIV.

"Clinical trial results have demonstrated that the effectiveness of preventive oral medications can range with results as high as 75 percent effective to as low as ineffective, and a lot of that variability appears to hinge on the patient's ability to take the pills as prescribed," says study researcher Martin
Markowitz, a professor at Rockefeller University and ADARC. "Long acting cabotegravir has the potential to create an option that could improve adherence by making it possible to receive the drug by injection once every three months."

Developed by ViiV Healthcare and GlaxoSmithKline, and previously known as GSK744 LA, cabotegravir is an antiretroviral drug. Antiretrovirals interfere with HIV's ability to replicate itself using a host cell and they are used to treat an HIV infection or to prevent those at high risk from acquiring it in the first place.

Long-acting drug effectively prevents HIV-like infection in monkeys 

In continuation of my update on Century-old drug reverses autism-like symptoms in fragile X mouse model.

In continuation of my update on Suramin

Researchers previously reported that a drug used for almost a century to treat trypanosomiasis, or sleeping sickness, reversed environmental autism-like symptoms in mice. Now, a new study suggests that a genetic form of autism-like symptoms in mice are also corrected with the drug, even when treatment was started in young adult mice.

Century-old drug reverses autism-like symptoms in fragile X mouse model